A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer.

PURPOSE: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. RESULTS: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. CONCLUSIONS: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. ©2015 AACR.

Ultimate fate of oncology drugs approved by the us food and drug administration without a randomized Trial.

PURPOSE: To approve a new anticancer drug, the US Food and Drug Administration often requires randomized trials. However, several oncology drugs have been approved on the basis of objective end points without a randomized trial. We reviewed the long-term safety and efficacy of such agents. METHODS: We searched the Web site of the US Food and Drug Administration's Center for Drug Evaluation and Research and MEDLINE for initial applications of investigational anticancer drugs from 1973 through 2006. RESULTS: Overall, 68 oncology drugs, excluding hormone therapy and supportive care, were approved, including 31 without a randomized trial. For these 31 drugs, a median of two clinical trials (range, one to seven) and 79 patients (range, 40 to 413) were used per approval. Objective response was the most common end point used for approval; median response rate was 33% (range, 11% to 90%). Thirty drugs are still fully approved. United States marketing authorization for one drug, gefitinib (an epidermal growth factor receptor [EGFR] inhibitor), was rescinded after a randomized trial showed no survival improvement; however, this trial was performed in unselected patients, and it was subsequently demonstrated that patients with EGFR mutation are more likely to respond. Nineteen of the 31 drugs have additional uses (per National Comprehensive Cancer Network or National Cancer Institute Physician Data Query guidelines), and subsequent formal US Food and Drug Administration approvals were obtained for 11 of these (range, one to 18 new indications). No drug has demonstrated safety concerns. CONCLUSION: Nonrandomized clinical trials with definitive end points can yield US Food and Drug Administration approvals, and these drugs have a reassuring record of long-term safety and efficacy.

Predictors of access to palliative care services among patients who died at a Comprehensive Cancer Center.

PURPOSE: Palliative care services can decrease physical and psychosocial distress in patients with advanced cancer. However, most patients with cancer die without access to palliative care services (APCS), and patterns of referral are not well understood. The purpose of this study was to determine predictors of patients' access to palliative care. PATIENTS AND METHODS: We reviewed patient records from the computerized database at UT M. D. Anderson Cancer Center over 2 (2003 and 2004) to determine differences in characteristics and outcomes between patients with and without APCS. APCS was defined as a palliative care consultation and follow-up or transfer to the palliative care unit. RESULTS: A total of 499 of 1453 (34%) inpatients who died at our cancer center had APCS. There were no significant differences in race, age, or insurance status between the APCS groups. The two major predictors of a low rate of APCS were hematologic malignancies (20% rate of APCS versus 44% for solid tumors, p < 0.0001) and intensive care unit (ICU) admission (15% versus 52% for non-ICU admission, p < 0.0001). Patients with hematologic malignancies who were admitted to the ICU had the lowest APCS rate (10%, p < 0.0001). The median relative cost of care per patient for decedents with APCS was 0.62 compared to non-referred patients (p < 0.0001). CONCLUSION: APCS was lower among patients with hematologic malignancies and those admitted to the ICU. APCS resulted in a lower cost of care. Mortality in comprehensive cancer centers is quite variable among different primary malignancies. More research is needed to better define patterns of referral.

Characteristics, findings, and outcomes of palliative care inpatient consultations at a comprehensive cancer center.

PURPOSE: There is limited information available about the role and effect of a palliative care consultation service (mobile team, MT) in patient care. The purpose of this retrospective chart review was to determine the characteristics, findings, and outcomes of patients referred to MT in a comprehensive cancer center and to thereby gain information about its role in this setting. PATIENTS AND METHODS: The study group was 61 consecutive patients assessed by one MT during 2-month period. We reviewed their charts for information about demographic and disease features, reasons for consultation, findings, interventions, and outcomes. RESULTS: Patients were mainly referred by thoracic (n = 21; 34%), genitourinary (n = 10; 16%), and gynecology (n = 9; 15%) services. The majority of patients had metastatic disease (n = 56; 92%). Evaluation of pain was the main reason for the consultation (n = 47; 77%) followed by delirium (n = 10; 16%). The MT found a total of 449 symptoms (median 8 per patient), whereas the referring team had mentioned only 86 (1 symptom per patient) in their requests. Twenty patients (38%) screened positive for a history of alcoholism. The MT diagnosed delirium in 34 patients (56%) and frequently found features of opioid-induced side effects, such as sedation (n = 46; 75%), constipation (n = 43; 70%), and confusion (n = 34; 56%). Frequent MT interventions were: administration of neuroleptics (n = 33; 54%), opioid rotation (n = 30; 49%), and enema (n = 33; 54%). Seventeen patients (28%) showed symptoms improvement within 24 hours and 23 patients within 72 hours (38%). Twenty-five patients (41%) required transfer to the palliative care unit. CONCLUSIONS: The MT had a positive impact on these patients' care in terms of clinical findings and outcomes. Further investigations are warranted.